title: The novel anticancer agent JNJ-26854165 induces cell death through inhibition of cholesterol transport and degradation of ABCA1.
abstract: JNJ-26854165 (serdemetan) has previously been reported to inhibit the function of the E3 ligase human double minute 2, and we initially sought to characterize its activity in models of mantle cell lymphoma (MCL) and multiple myeloma (MM). Serdemetan induced a dose-dependent inhibition of proliferation in both wild-type (wt) and mutant (mut) p53 cell lines, with IC50 values from 0.25 to 3 μM/l, in association with an S phase cell cycle arrest. Caspase-3 activation was primarily seen in wtp53-bearing cells but also occurred in mutp53-bearing cells, albeit to a lesser extent. 293T cells treated with JNJ-26854165 and serdemetan-resistant fibroblasts displayed accumulation of cholesterol within endosomes, a phenotype reminiscent of that seen in the ATP-binding cassette subfamily A member-1 (ABCA1) cholesterol transport disorder, Tangiers disease. MM and MCL cells had decreased cholesterol efflux and electron microscopy demonstrated the accumulation of lipid whorls, confirming the lysosomal storage disease phenotype. JNJ-26854165 induced induction of cholesterol regulatory genes, sterol regulatory element-binding transcription factor-1 and -2, liver X receptors α and β, along with increased expression of Niemann-Pick disease type-C1 and -C2. However, JNJ-26854165 induced enhanced ABCA1 turnover despite enhancing transcription. Finally, ABCA1 depletion resulted in enhanced sensitivity to JNJ-26854165. Overall, these findings support the hypothesis that serdemetan functions in part by inhibiting cholesterol transport and that this pathway is a potential new target for the treatment of MCL and MM.
authors.affiliation: The Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Dongmin
authors.initials: D
authors.lastname: Gu
authors.forename: Chad C
authors.initials: CC
authors.lastname: Bjorklund
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Tarig
authors.initials: T
authors.lastname: Bashir
authors.forename: Veronique
authors.initials: V
authors.lastname: Vreys
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D005434:Flow Cytometry; D020868:Gene Silencing / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014363:Tryptamines / Q000494:pharmacology*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D011838:Radiation-Sensitizing Agents; D014363:Tryptamines; C568210:JNJ 26854165; D002784:Cholesterol; D053148:Caspase 3